Use of steroid derivatives as antifertility agents

ABSTRACT

Derivatives of certain 16 Alpha , 17 Alpha -dihydroxysteroids of the pregnane series are described. These steroids are useful for controlling fertility in warmblooded female animals.

United States Patent Milton David Heller New City;

John Anthony Coppola, Sufiern; Seymour Bernstein, New City, all of N.Y. 865,961

Oct. 13, 1969 Sept. 21, 1971 American Cyanamid Company Stamford, Conn.

Inventors Appl. No. Filed Patented Assignee USE OF STEROID DERIVATIVES AS Field of Search [5 6] References Cited FOREIGN PATENTS 1,060,632 3/1967 Great Britain.

1,081,358 8/1967 Great Britain.

Primary Examinn-Richard L. Huff Attorney-Ernest Y. Miler ABSTRACT: Derivatives of certain 16a, l7a-dihydroxysteroids of the pregnane series are described. These steroids are useful for controlling fertility in warmblooded female animals.

USE OF STEROID DERIVATIVES AS ANTIFERTILITY AGENTS This invention relates to the use of derivatives of chloropregnane aeetonides as antifertility agents. 5

The compounds useful as antifertility agents may be illustrated by the following formula:

wherein X is selected from the group consisting of hydrogen h andc lorme,

is a trivalent radical selected from the group consisting of A ...M.- R is lower alkyl; R is selected from the group consisting of lower alkyl and phenyl and indicates a double or single bond. Lower alkyl is intended to include those having one to four carbon atoms. The above-described active components form a part of novel compositions containing a pharmaceutically acceptable carrier.

Some of the active components of the present invention can be prepared, for example, by the methods described in US. Pat. No. 3,21 1,727, issued Oct. 12, 1965. Others are prepared by methods herein described.

The compositions of this invention provide a convenient mode of contraception through the use of an orally administered composition without inducing permanent reproductive sterility. It has been found that when compositions containing the above-described active components were orally administered at sufficient dosage described hereinafter for l0 days to adult female rats which were cohabited with fertile male rats, pregnancy was prevented in all instances. Moreover, no accompanying maternal lethality was observed.

Accordingly, this invention includes within its scope the new compositions of matter for the control of mammalian female sexual reproduction and to methods of their administration. It is indicated that the favorable results achieved in rats with these compositions will relate to similar effects in There are several points of contraceptive attack during the normal processes of mammalian female reproduction. These points include ovulation blockade, interference with the fertilization of the ovum by sperm, interference with the normal transport of ova and/or zygotes in the reproductive tract, prevention of embryo implantation disruption of the maternal response to embryonic implantation, and maternal failure to support embryonic survival. While the exact mechanism or mechanisms which take place with the active ingredient in effecting contraception is not clear, it is known that the compositions of this invention prevent conception by one or more of the above-mentioned occurrences It is not intended, however, that the present invention be limited to any particular theory as to mechanism of contraception.

While the method of administering the active component of the novel therapeutic compositions of the present invention is not limited to oral administration alone, a decided practical advantage of the invention is that the active ingredient may be administered orally in any convenient manner. This however, does not preclude the used of the present compositions intraperitoneally or by other nonoral means. The compound, preferably, may be taken orally, for example, with an inert diluent or with an assimilable edible carrier, or by use of a pharmaceutically acceptable carrier compressed into tablets, or enclosed in hard or soft gelatin capsules. Other compositions include, for example, suspensions, syrups, elixirs, emulsions, wafers, chewing gum or the like. Obviously, in addition to the therapeutic active ingredient there may be present excipients, binders, fillers and other inert ingredients necessary in the formulation of the desired pharmaceutical compositions. Preferred compositions or preparations according to the present invention are prepared so that a dosage unit form contains between about 0.005 milligrams and about 200 milligrams of the active component. These dosage unit forms may be administered one or more times per day, on a daily basis, during the period antifertility effect is desired.

The amount of a single dose or of a daily dose to produce the desired level of efficacy should be such as to give a proportionate dosage of from about 0.0009 mg. to l0 mg./kg./day of active component. In terms of total weight of active component the daily dosage for warmblooded animals of, for example, 60 kilograms would amount to from about 0.05 mg. to 60 mg. The dosage regimen may be adjusted to provide optimumresponse with the least amount of active ingredients.

The following examples illustrate the method of administering the novel compositions of this invention their antifertility effect in female rats, preparation of some of the compounds and also various formulations for oral administration.

EXAMPLE 1 Adult Wistar strain rats, maintained on a standard diet of laboratory rat pellets and water, ad libitum, are used. Graded doses of 11/3, 2l-triChl0r0-l6a, l7rx-isopropylidenedioxypregna-l,4, 6-triene-3,20-dione are orally administered once daily for 10 days to female rats. The composition is composed of propylene glycol and an appropriate amount of active ingredient so that the desired dose is given in a 0.25-ml. volume. Control rats are given propylene glycol without the active ingredients. From the first day of treatment, the females are placed with fertile males in a ratio of four females to three males. Four days after-the last dose the females were sacrificed and autopsied and uterine fetal implantation sites were counted. Results of this study are given in table l below:

TABLE 1 TABLE V No. Rats Pregnant] Dose, mgJkgJday Nov Rats Treated EXAMPLE 2 Following the procedure set forth in example 1 and using 9a, llfi, 21-trichloro-l6a, l7a-isopropylidenedioxypregna- 1,4-diene-3,20-dione as the antifertility agent, the following results are obtained.

TABLE II No. Rats Pregnant] Dose, mgJkgJday No. Rats Treated EXAMPLE 3 Using the procedure set forth in example 1 and 90/, HB- dichlorol 60/, l7a-isopropylidenedioxypregnal ,4-diene- 3,20-dione as the antifertility agent, the following results are obtained.

TABL "I No. Rats Pregnant] Dose, mgJkgJday No. Rats Treated EXAMPLE 4 Following the procedure set forth in example 1 and using 21 -chloro-16a, 17oz-isopropylidenedioxypregna-l ,4,6,9(l l)- tetraene-3,20-dione as the antifertility agent, the following results are obtained.

TABLE 1v 7 W No. Rats Pregnant] Dose, rng./kg./day No. Rats Treated EXAMPLE 5 When the procedure set forth in example 1 is used and 9a, 1 1B, 2 l -trichlorol 60/, l7aisopropylidenedioxypregn-4-ene- 3,20-dione is the antifertility agent, the following results are obtained No. Rats Pregnant/ Dose, mg./kg./day No. Rats Treated EXAMPLE 6 Preparation of 9a, 1 1B, 2 l -Trich|oro-l6a, l7adihydroxypre gna- 1 ,4,6-triene-3,20a-dione A solution of mg. of 9a, 113, 2l-trichloro-l6a, 17aisopropylidenedioxypregna-l,4,6-triene-3,20-dione in 5.5 ml. of 70 percent formic acid is refluxed for 2 hours. The resultant solution is poured into ice water and the mixture is filtered. The residue is recrystallized from acetone-hexane to give 90/, 1 1B, -2l-trichloro-l6a, l7a-dihyroxypregna-l ,4,6-triene- 3,20-dione.

EXAMPLE 7 Preparation of Actophenide derivative of 90/, 1 1B, 2 l trichloro-16a, /1, 4, 6

EXAMPLE 8 Preparation of 16a, 17a-(2'Butylideneioxy)-9a, 1 1B, 21- trichloro-pregnal ,4,6-triene-3,20-dione To a suspension of lOO mg. of 9a, 113, 2l-tr1'chloro-l6al7a-dihydroxypregna-l,4,6-triene-3,20-dione, the product of example 6, in 15 ml. of methylethylketone is added 0.05 ml. of 72 percent perchloric acid and the mixture stirred at room temperature 2 hours. The resultant solution is neutralized with sodium bicarbonate solution and after addition of water, the methylethylketone is evaporated under reduced pressure. The resultant filtered crystals are 1611, l7a-(2'-butylidenedioxy)- 9a, 1 1B, 2 l -trichloropregna-l ,4,6-triene-3,20-dione.

EXAMPLE 9 Hard Gelatin Capsules Grams diene-LLZO-dione Cornstarch 1,977 Magnesium stcarate, powder l0 Talc 10 The finely divided ingredients are mixed thoroughly and then encapsulated in 10,000 two-piece hard gelatin capsules each containing 0.3 mg. of 9a, 113, 21-trichIoro-l6a. 17B- isopropylidenedioxypregna-1,4-diene-3,20-dione.

EXAMPLE Twenty thousand tablets each containing 0.05 mg. of 9a, l 13, b2 1 -trichloro- 1 6a, l7a-isopropylidenedioxypregnal,4,6-triene-3,20-dione are prepared from the following ingredients:

Five hundred one-piece soft gelatin for oral use each containing 90 mg. of 9a, l lfi-dichloro-l6a, l7a-isopropylidenedioxypregna-l ,4-diene-3,20-dione are prepared by first dispersing 45 grams of the compound in sufficient corn oil to render the material capsulatable and then encapsulating in the usual manner.

EXAMPLE 12 Using the formulation of example 9 and 3 g. of the acetophemide derivative of 9a, 1 1B, 2l-trichloro- 1 6a, dihydroxypregna-l ,4,6-triene-3,20-dione as the active component, capsules are obtained which contain 0.3 mg. each.

We claim:

1. A method for controlling fertility in warmblooded female animals which comprises orally administering to said animals a contraceptively effective amount of 901, 1 IB, 2l-trichloro-l6a l7a-isopropylidenedioxypregna-4-ene3,20-dione and a pharmaceutically acceptable carrier.

2. A method for controlling fertility in warmblooded female animals which comprises orally administering to said animals a contraceptively effective amount of 9a, llfl2l-trichloro-l6a, l7a-isopropylidenedioxypregnal ,4-diene-3,20-dione and a pharmaceutically acceptable carrier.

3. A method for controlling fertility in warmblooded female animals which comprises orally administering to said animals a contraceptively effective amount of 9a, 1 1B, 2l-trichloro-l6a l7a-isopropylidenedioxypregnal ,4,6-triene-3,20-dione and a pharmaceutically acceptable carrier.

4. A method for controlling fertility in warmblooded female animals which comprises orally administering to said animals a contraceptively effective amount of 9a-chloro- 1 6a] 7aisopropylidenedioxypregna-l, 4, 6, 9 (1 l)tetraene-3,20-dione and a pharmaceutically acceptable carrier. 

2. A method for controlling fertility in warmblooded female animals which comprises orally administering to said animals a contraceptively effective amount of 9 Alpha , 11 Beta 21-trichloro-16 Alpha , 17 Alpha -isopropylidenedioxypregna-1,4-diene-3,20-dione and a pharmaceutically acceptable carrier.
 3. A method for controlling fertility in warmblooded female animals which comprises orally administering to said animals a contraceptively effective amount of 9 Alpha , 11 Beta , 21-trichloro-16 Alpha , 17 Alpha -isopropylidenedioxypregna-1,4,6-triene-3,20-dione and a pharmaceutically acceptable carrier.
 4. A method for controlling fertility in warmblooded female animals which comprises orally administering to said animals a contraceptively effective amount of 9 Alpha -chloro-16 Alpha 17 Alpha -isopropylidenedioxypregna-1, 4, 6, 9 (11)tetraene-3,20-dione and a pharmaceutically acceptable carrier. 